Cyclopamine, a natural product isolated from Veratrum californicum, has emerged as a significant pharmacological tool to validate the Hedgehog (Hh) pathway in cancer. Cyclopamine directly acts on SMO and inhibits tumor growth in several murine models of pancreatic, medulloblastoma, prostate, small cell lung, and digestive tract cancers. However, the clinical development of cyclopamine as a therapeutic in cancer is hampered by its poor solubility, acid sensitivity, and weak potency relative to other reported small-molecule Hh antagonists.
There has been considerable focus on the development of novel cyclopamine analogues with improved potency, and improved pharmacokinetic and pharmaceutical properties relative to cyclopamine (s ee, for example, U.S. Pat. Nos. 7,230,004 and 7,407,967, incorporated herein by reference). From that effort, a seven-membered D-ring sulfonamide analogue of cyclopamine, IPI-926, emerged as a clinical development candidate (see Tremblay et al., “Discovery of a Potent and Orally Active Hedgehog Pathway Antagonist (IPI-926)” J. Med. Chem. (2009) 52:4400-4418, incorporated herein by reference). Large quantities of IPI-926 are required for clinical development. Moreover, other promising amino analogues can be synthesized following routes similar to that used to generate IPI-926.
